ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1730C>T (p.Ser577Leu) (rs56185292)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656864 SCV000149374 uncertain significance not provided 2018-04-03 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1730C>T at the cDNA level, p.Ser577Leu (S577L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant, also defined as MLH1 1007C>T (Ser336Leu) using alternate nomenclature, was observed in at least three individuals undergoing hereditary cancer risk assessment for Lynch syndrome (Chao 2008, Lagerstedt-Robinson 2016). MLH1 Ser577Leu was also identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. MLH1 Ser577Leu was observed at an allele frequency of 0.06% (11/18852) in individuals of East Asian ancestry in large population cohorts (Lek 2016). MLH1 Ser577Leu is located within the regions of interaction with EXO1 and PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2010, Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MLH1 Ser577Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115465 SCV000184371 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000226023 SCV000284028 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 577 of the MLH1 protein (p.Ser577Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs56185292, ExAC 0.07%). This variant has been observed in individuals affected with Lynch syndrome (PMID: 27601186), and an individual affected with pancreatic ductal adenocarcinoma (PMID: 28767289). Additionally, this variant has been observed in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 127619). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000411289 SCV000488812 uncertain significance Lynch syndrome II 2016-06-23 criteria provided, single submitter clinical testing
Color RCV000115465 SCV000537587 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-08 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000121362 SCV000592418 uncertain significance not specified 2015-05-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121362 SCV000601362 uncertain significance not specified 2017-02-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515241 SCV000611399 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2017-05-23 criteria provided, single submitter clinical testing
ITMI RCV000121362 SCV000085543 not provided not specified 2013-09-19 no assertion provided reference population

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